Clinical Trial: Gamma-Secretase Inhibitor RO4929097 and Cediranib Maleate in Treating Patients With Advanced Solid Tumors

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: A Phase 1, Pharmacokinetic and Pharmacodynamic Study of the Combination of RO4929097 and Cediranib in Patients With Advanced Solid Tumors

Brief Summary: This phase I clinical trial is studying the side effects and best dose of giving gamma-secretase inhibitor RO4929097 and cediranib maleate together in treating patients with advanced solid tumors. Gamma-secretase inhibitor RO4929097 and cediranib maleate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Cediranib maleate also may stop the growth of tumor cells by blocking blood flow to the tumor.

Detailed Summary:

PRIMARY OBJECTIVES:

I. To determine the tolerability, maximum tolerated dose (equivalent to the recommended phase II dose), and safety profile of RO4929097 (gamma-secretase inhibitor RO4929097) in combination with cediranib (cediranib maleate) in patients with advanced malignancies.

SECONDARY OBJECTIVES:

I. To obtain pharmacokinetic (PK) profiles for RO4929097 when administered alone and for RO492907 and cediranib in combination, in order to evaluate for interactive effects in PK (if any) between these two agents.

II. To evaluate pharmacodynamic (PD) effects of RO492907 when administered alone and in combination, with the goal of identifying potential predictive and PD markers that need further exploration and validation in future trials.

III. To assess for preliminary antitumor efficacy of this drug combination, especially in breast cancer, malignant melanoma, colorectal cancer, pancreatic cancer, kidney cancer, high grade glioma, non-small-cell lung cancer, and ovarian cancer.

OUTLINE: This is a dose-escalation study.

Patients receive gamma-secretase inhibitor RO4929097 orally (PO) once daily (QD) on days 1-3, 8-10, and 15-17 (days 1-3, 8-10, 15-17 22-24, 29-31, and 36-38 of course 1) and cediranib maleate PO QD on days 1-21 (days 22-42 course 1 only). Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks.


Sponsor: National Cancer Institute (NCI)

Current Primary Outcome:

  • Recommended phase II dose of gamma-secretase inhibitor RO4929097 defined as the dose level at which < 1/6 patients experience dose-limiting toxicity as graded by the National Cancer Institute (NCI) CTCAE version 4.0 [ Time Frame: 42 days ]
    Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest.
  • Incidence of adverse events as graded by the NCI CTCAE version 4.0 [ Time Frame: Up to 4 weeks post-treatment ]
    Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest.


Original Primary Outcome: Recommended phase II dose and safety profile of gamma-secretase inhibitor RO4929097

Current Secondary Outcome:

  • PK profiles for both drugs [ Time Frame: On days 1, 10, 22, and 38 of course 1, and then on day 1 of courses 2-6 ]
    PK parameters will be calculated by non-compartmental methods.
  • PD effects of gamma-secretase inhibitor RO4929097 when administered alone and in combined with cediranib maleate [ Time Frame: On days 1 and 22 of course 1 and on day 1 of course 2 ]
    Standard descriptive statistics, such as the mean, median, range and proportion, will be used to summarize the patient sample and to estimate parameters of interest. Ninety-five percent confidence intervals will be provided for estimates of interest where possible.
  • Preliminary antitumor efficacy [ Time Frame: Up to 4 weeks post-treatment ]
    Summary statistics, such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Objective response to treatment will be assessed using the RECIST criteria 1.1.


Original Secondary Outcome:

  • Pharmacokinetic profiles for both drugs
  • Pharmacodynamic effects of both drugs
  • Preliminary antitumor efficacy


Information By: National Cancer Institute (NCI)

Dates:
Date Received: May 25, 2010
Date Started: May 2010
Date Completion:
Last Updated: December 22, 2014
Last Verified: November 2014